Accepted Article

Article Type: Invited Review

A Perspective Overview of Clinically Approved Oral Antidiabetic Agents for the Treatment of Type 2 Diabetes Mellitus

Zhi-Xu He1, Zhi-Wei Zhou2, Yinxue Yang3, Tianxin Yang4, Si-Yuan Pan5, Jia-Xuan Qiu6,*, and

Shu-Feng Zhou2,*

1

Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering

Research Center & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang 550004, Guizhou, China; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, Florida 33612, USA; 3Department of Colorectal Surgery,

General Hospital of Ningxia Medical University, Yinchuan City, Ningxia 750004, China; 4

Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical

Center, Salt Lake City, UT 84132, USA; 5Department of Chinese Medicinal Pharmacology, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China; and

6

Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang

University, Nanchang 330006, Jiangxi, China.

*Corresponding to: Professor Shu-Feng Zhou, MD, PhD Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, Florida 33612. Tel: 813 974-6276; Fax: 813 905-9885. Email: [email protected]. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/1440-1681.12332 This article is protected by copyright. All rights reserved.

and

Accepted Article

Professor Jia-Xuan Qiu, MD & PhD Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang

University, 17 Yongwai Main St, Nanchang 330006, Jiangxi, China. Tel: +86 791 869-2531; Fax: +86 791 869-2745. Email: [email protected].

Running title: Current drugs for treatment of T2DM.

SUMMARY

Type 2 diabetes mellitus (T2DM) is caused by insulin resistance and characterised by progressive pancreatic β-cell dysfunction. This article aimed to review the application and limitation of currently approved oral drugs for the treatment of T2DM. The data were retrieved from the literature and well recognized drug related databases. While lifestyle modifications and metformin are the cornerstone of the initial management of T2DM, there is an increasing array of second and third-line pharmacological agents including sulphonylureas, insulin, thiazolidinediones/glitazones, α-glucosidase inhibitors, glucagon-like peptide-1 agonists, dipeptidyl peptidase-IV inhibitors, and the amylin receptor agonist pramlintide.Current T2DM treatment focuses on the reduction of blood glucose level via different mechanisms involving nuclear hormone receptors, nucleic acid binding proteins, transcription factors, voltage gated K+ channel, glucosidase, G-protein coupled receptor

and non-receptor serine/threonine protein kinase. Extensive effort is needed to address the pathogenesis of T2DM, which may facilitate the development of new therapies and identification of new therapeutic targets to overcome the shortcomings of currently available drugs for T2DM and achieve therapeutic goals.

Keywords: T2DM, biguanide, sulfonylurea, DDP-4, metoformin.

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INTRODUCTION

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Diabetes mellitus (DM) is a major health problem around the world, with continued expansion of DM associated with increased morbidity and mortality, reduced quality of life, and increased health care costs. It is placing a great burden on individuals, family, and society. Based on the data from the 2014 National Diabetes Statistics Report in US (http://www.cdc.gov//diabetes/pubs/statsreport14.htm), 29.1 million children and adults (i.e. 9.3% of the population) have diabetes; and 1.7 million new cases of diabetes are diagnosed in people aged 20 years and older in 2012. A total of 28.9 million or 12.3% of US people aged 20 years and older have diabetes. Notably, there are 8.1 million people (27.8% of people) with diabetes are undiagnosed. In adults, type 2 diabetes mellitus (previously called non–insulin-dependent diabetes mellitus or adult-onset diabetes; T2DM) accounts for about 90% to 95% of all diagnosed cases of diabetes. T2DM is a chronic metabolic disorder characterized by progressive hyperglycaemia secondary to declining β-cell function, and usually accompanied by a reduced sensitivity to insulin in peripheral tissues; such as liver and muscle.1 If untreated or not managed well, long term hyperglycaemia can lead to increased risk of macrovascular (cardiovascular, cerebrovascular and peripheral vascular disease) and microvascular (nephropathy, neuropathy, and retinopathy) complications. Effectiveness of T2DM treatment therapy is often determined by indicators such as glycosylated haemoglobin (HbA1C) level.2 The American Diabetes Association recommends an HbA1C target level of ≤ 7% in diabetic patients.

T2DM is often treated with insulin sensitisers (e.g. thiazolidinediones), insulin secretagogues

(e.g. sulfonylureas and meglitinides), and external insulin delivery (insulin analogues). A number of new compounds for the treatment of T2DM are under development of different stages. This article aimed to discuss currently approved oral agents for the treatment of T2DM. Data on current clinical drugs for T2DM treatment were extracted from the US Food and Drugs Administration website,

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kidney disorders, lung disease and liver disease. Metformin is often used in combination with other

Accepted Article

oral anti-diabetic drugs. In US, the most popular combination was metformin with rosiglitazone, sold as Avandamet by GlaxoSmithKline since October 2002. Metformin is also used in combination with pioglitazone (Actoplus Met, approved by FDA in August 2005), the sulfonylureas glipizide (Metaglip, approved in October 2002) and glibenclamide/glyburide (Glucovance, approved in September 2008), the dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin (Janumet, approved in March 2007) and saxagliptin (Kombiglyze XR, approved in November 2010), and the meglitinide repaglinide (PrandiMet, approved in June 2008). In Europe, the combined use of metformin with the DPP-4 inhibitor linagliptin was approved in May 2005 with the trade name of Jentadueto. This combination was also approved by the FDA in February 2012. The EMEA has also approved a new combination of metformin and the DPP-4 inhibitor vildagliptin (Eucreas) in February 2008. Furthermore, the FDA approved the combination of metformin with alogliptin under the trade name of Kazano in January 2013.

BILE ACID SEQUESTRANTS

Cholestyramine and colestipol are first-generation bile acid sequestrants and antihyperlipidemic agents that currently have a limited use because of their relatively weak effect on lowering low density-lipoprotein-cholesterol (LDL-C) and poor tolerability.24,25 The second-generation bile acid sequestrants such as colesevelam and colestimide (also called colestilan, approved for treating T2DM in Japan in 1999) have a glucose-lowering effect and improved tolerance, which has led to re-evaluation of their application as oral anti-diabetic agents.

Colesevelam (Welchol) is a bile acid binding resin sequestrant developed by Genzyme and

marketed in the US since 2008 by Daiichi Sankyo. Colesevelam is indicated as an adjunct to diet and exercise to reduce elevated LDL-C in patients with primary hyperlipidaemia as monotherapy and to improve glycaemic control in T2DM, including in combination with a statin.26,27 The

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AMYLIN RECEPTOR AGONISTS

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Amylin inhibits postprandial glucagon secretion and delays gastric emptying, thereby modifying postprandial hyperglycaemia in diabetic patients which presumably adds to overall glycaemic control without a concomitant increase in the risk of severe hypoglycaemia.13 Amylin replacement may therefore improve glycaemic control in diabetes mellitus.6 However, human amylin exhibits

physicochemical properties predisposing the peptide hormone to aggregate and form amyloid fibres, which makes it unsuitable for medical use. Pramlintide (Symlin) is a relatively new adjunct treatment for diabetes (both Type 1 and 2), developed by Amylin Pharmaceuticals Inc.14 It is

derived from amylin, a hormone that is released from pancreatic β-cells into the bloodstream. Through mimicking the activity of amylin, pramlintide acts to improve glycaemic control through modulation of the rate of gastric emptying, prevention of post-prandial rise in glucagon levels, and by increasing sensations of satiety, thereby reducing caloric intake and potentiating weight loss.15,16

ANORECTIC

Benfluorex (Figure 2, Mediator) is an anorectic and hypolipidemic agent that is structurally related to fenfluramine developed by a French pharmaceutical company, Servier. Benfluorex inhibits gluconeogenesis is, at least in part, ascribed to a decrease in mitochondrial β-oxidation. Benfluorex

decreases acetyl-CoA concentration, reducing pyruvate carboxylase activity and releases its inhibitory effect on pyruvate dehydrogenase. Benfluorex also decreases the ATP/ADP and NAD+/NADH ratios, leading to a reduced gluconeogenic flux at the level of 3-phosphoglycerate kinase and GAPDH ( Table 1).17 Two clinical studies have shown that it may improve glycaemic control and decrease insulin resistance in patients with poorly controlled T2DM. On 18 December 2009, the European Medicines Agency (EMEA) recommended the withdrawal of all medicines containing benfluorex in the European Union due to the risk of heart valve disease.18

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Accepted Article

26

Emami Riedmaier A, Fisel P, Nies AT, Schaeffeler E, Schwab M. Metformin and cancer: from the old medicine cabinet to pharmacological pitfalls and prospects. Trends in pharmacological sciences 2013; 34: 126-35.

27

Hemmingsen B, Christensen LL, Wetterslev J, Vaag A, Gluud C, Lund SS, Almdal T. Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses. Bmj 2012; 344: e1771.

28

Edwards KL, Stapleton M, Weis J, Irons BK. An update in incretin-based therapy: a focus on glucagon-like peptide-1 receptor agonists. Diabetes technology & therapeutics 2012; 14: 951-67.

29

Stonehouse AH, Darsow T, Maggs DG. Incretin-based therapies. Journal of diabetes 2012; 4: 55-67.

30

Dailey MJ, Moran TH. Glucagon-like peptide 1 and appetite. Trends in endocrinology and metabolism: TEM 2013; 24: 85-91.

31

Russell S. Incretin-based therapies for type 2 diabetes mellitus: a review of direct comparisons of efficacy, safety and patient satisfaction. International journal of clinical pharmacy 2013; 35: 159-72.

32

Subbarayan S, Kipnes M. Sitagliptin: a review. Expert opinion on pharmacotherapy 2011; 12: 1613-22.

33

Holt RI, Barnett AH, Bailey CJ. Bromocriptine: old drug, new formulation and new indication. Diabetes, obesity & metabolism 2010; 12: 1048-57.

34

Pijl H, Edo AM. Modulation of monoaminergic neural circuits: potential for the treatment of type 2 diabetes mellitus. Treatments in endocrinology 2002; 1: 71-8.

35

de Leeuw van Weenen JE, Parlevliet ET, Maechler P, Havekes LM, Romijn JA, Ouwens DM, Pijl H, Guigas B. The dopamine receptor D2 agonist bromocriptine inhibits glucosestimulated insulin secretion by direct activation of the α2-adrenergic receptors in β-cells. Biochemical pharmacology 2010; 79: 1827-36.

36

Derosa G, Maffioli P. alpha-Glucosidase inhibitors and their use in clinical practice. Archives of medical science : AMS 2012; 8: 899-906.

37

Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2009; 52: 17-30.

38

Narender T, Madhur G, Jaiswal N, Agrawal M, Maurya CK, Rahuja N, Srivastava AK, Tamrakar AK. Synthesis of novel triterpene and N-allylated/N-alkylated niacin hybrids as alpha-glucosidase inhibitors. European journal of medicinal chemistry 2013; 63: 162-9.

39

Nauck M, Horton E, Andjelkovic M, Ampudia-Blasco FJ, Parusel CT, Boldrin M, Balena R, Group TeS. Taspoglutide, a once-weekly glucagon-like peptide 1 analogue, vs. insulin glargine titrated to target in patients with Type 2 diabetes: an open-label randomized trial. Diabetic medicine : a journal of the British Diabetic Association 2013; 30: 109-13.

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Accepted Article

40

Black C, Donnelly P, McIntyre L, Royle PL, Shepherd JP, Thomas S. Meglitinide analogues for type 2 diabetes mellitus. The Cochrane database of systematic reviews 2007: CD004654.

41

Scott LJ. Repaglinide: a review of its use in type 2 diabetes mellitus. Drugs 2012; 72: 24972.

42

Tentolouris N, Voulgari C, Katsilambros N. A review of nateglinide in the management of patients with type 2 diabetes. Vascular health and risk management 2007; 3: 797-807.

43

Hanif W, Kumar S. Nateglinide: a new rapid-acting insulinotropic agent. Expert opinion on pharmacotherapy 2001; 2: 1027-31.

44

Phillippe HM, Wargo KA. Mitiglinide for type 2 diabetes treatment. Expert opinion on pharmacotherapy 2013; 14: 2133-44.

45

Rosenwasser RF, Sultan S, Sutton D, Choksi R, Epstein BJ. SGLT-2 inhibitors and their potential in the treatment of diabetes. Diabetes, metabolic syndrome and obesity : targets and therapy 2013; 6: 453-67.

46

Tahrani AA. SGLT-2 inhibitors as second-line therapy in type 2 diabetes. The lancet. Diabetes & endocrinology 2014; 2: 678-9.

47

Diamant M, Morsink LM. SGLT2 inhibitors for diabetes: turning symptoms into therapy. Lancet 2013; 382: 917-8.

48

Nomura S, Sakamaki S, Hongu M, Kawanishi E, Koga Y, Sakamoto T, Yamamoto Y, Ueta K, Kimata H, Nakayama K, Tsuda-Tsukimoto M. Discovery of canagliflozin, a novel Cglucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. Journal of medicinal chemistry 2010; 53: 6355-60.

49

Elkinson S, Scott LJ. Canagliflozin: first global approval. Drugs 2013; 73: 979-88.

50

Babu A. Canagliflozin for the treatment of type 2 diabetes. Drugs of today 2013; 49: 363-76.

51

Hussey EK, Dobbins RL, Stoltz RR, Stockman NL, O'Connor-Semmes RL, Kapur A, Murray SC, Layko D, Nunez DJ. Multiple-dose pharmacokinetics and pharmacodynamics of sergliflozin etabonate, a novel inhibitor of glucose reabsorption, in healthy overweight and obese subjects: a randomized double-blind study. Journal of clinical pharmacology 2010; 50: 636-46.

52

Hussey EK, Clark RV, Amin DM, Kipnes MS, O'Connor-Semmes RL, O'Driscoll EC, Leong J, Murray SC, Dobbins RL, Layko D, Nunez DJ. Single-dose pharmacokinetics and pharmacodynamics of sergliflozin etabonate, a novel inhibitor of glucose reabsorption, in healthy volunteers and patients with type 2 diabetes mellitus. Journal of clinical pharmacology 2010; 50: 623-35.

53

Kurosaki E, Ogasawara H. Ipragliflozin and other sodium-glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes: preclinical and clinical data. Pharmacology & therapeutics 2013; 139: 51-9.

54

Imamura M, Nakanishi K, Suzuki T, Ikegai K, Shiraki R, Ogiyama T, Murakami T, Kurosaki E, Noda A, Kobayashi Y, Yokota M, Koide T, Kosakai K, Ohkura Y, Takeuchi M, Tomiyama H, Ohta M. Discovery of Ipragliflozin (ASP1941): a novel C-glucoside with benzothiophene structure as a potent and selective sodium glucose co-transporter 2 (SGLT2)

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mechanism by which colesevelam improves glycaemia are not yet determined but might involve

Accepted Article

enhanced meal-induced incretin secretion and altered farnesoid X receptor (FXR) signaling.25,27

DIPEPTIDYL PEPTIDASE 4 (DPP-4) INHIBITORS (GLIPTINS)

DPP-4 (also known as adenosine deaminase complexing protein 2 or CD26) cleaves the two Nterminal amino acids from peptides with a proline or alanine in the second position, inactivating both GLP-1 and gastric inhibitory polypeptide (GIP).28,29 Endogenously released GLP-1 has a short

biological half-life of 1.5−5 min and the serum half-life of GIP is approximately 7 min.30 Upon

secretion, GLP-1 and GIP are rapidly degraded and inactivated by DPP-4. Therefore, DPP-4 inhibitors (Figure 5) have been developed and used to prevent degradation of endogenously released GLP-1 and GIP, and consequently enhancing plasma level of active incretin in circulation, prolonging the actions of the incretin, leading to increased insulin level ( Table 1).31

Sitagliptin (Januvia) is the first DPP-4 inhibitor launched and was approved in October 2006

by the FDA. Sitagliptin was well tolerated and was not associated with hypoglycaemia.32 Further, a

fixed-dose combination tablet containing 50 mg sitagliptin and 500 or 1,000 mg metformin was approved by FDA in March 2007. Vildagliptin (Zomelis & Galvus) gained the approval from the EMEA in February 2008. Another DPP-4 inhibitor saxagliptin (Onglyza) was approved by the FDA in July 2009. The new DPP-4 inhibitor linagliptin (Tradjenta) was approved by the FDA in May 2011. Gemigliptin (Zemiglo, also previously known as LC15-0444) gained an approval in Korea in June 2012. Alogliptin (Nesina) obtained the approval in Japan in April 2010. In January 2013, the FDA approved the drug in three formulations: as a stand-alone, in combination with metformin (Kazano) or with pioglitazone (Oseni). Alogliptin as monotherapy or added to metformin, pioglitazone, glibenclamide, voglibose, or insulin therapy significantly improves glycaemic control compared with placebo in adult or elderly patients with inadequately controlled T2DM and the

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Accepted Article

Canagliflozin

Dapagliflozin

Empagliflozin

Epalrestat Glibenclamide

Gliclazide

Glimepiride Glipizide

(Day 14)

0.578

15 patients

400 mg/q.d. (Day 1)

2.420 ± 1.130

14 patients

400 mg/q.d. (Day 14)

2.560 ± 0.791

9 patients

50 mg/q.d. (Day 1)

0.426 ± 0.106

9 patients

50 mg/q.d. (Day 7)

0.536 ± 0.174

8 patients

100 mg/q.d. (Day 1)

1.096 ± 0.444

8 patients

100 mg/q.d. (Day 7)

1.227 ± 0.481

10 patients

300 mg/q.d. (Day 1)

3.480 ± 0.844

10 patients

300 mg/q.d. (Day 7)

4.678 ± 1.685

6 HV

2.5 mg/q.d.

0.029

6 HV

10 mg/q.d.

0.124

6 HV

20 mg/q.d.

0.265

6 HV

50 mg/q.d.

0.610

16 HV

50 mg/q.d.

0.532

16 patients

10 mg/b.i.d.

0.139

16 patients

25 mg/b.i.d.

0.326

30 patients

100 mg/b.i.d.

1.186

HV 110 patients

50 mg/q.d. 20 mg/q.d.a

110 patients

20 mg/q.d.c

9 Caucasian patients 10 aboriginal patients 8 patients

160 mg/q.d.b 160 mg/q.d.b 2 mg/q.d.

3.900 0.354 ± 0.033 0.360 ± 0.049 15.000 ± 3.700 14.100 ± 5.100

6 patients

10 mg/q.d.

10 HV (≤ age 25) 10 HV (≥ age 65) 15 patients (≥ age 65)

10 mg/q.d.a 10 mg/q.d.a 10 mg/q.d.a

1.8002.300 0.465 ± 0.146 0.399 ± 0.101 0.385 ± 0.150

(0.6010.60) 1.00 (0.502.50) 1.10 (0.504.50) 2.00 (1.004.00) 2.00 (1.005.00) 1.50 (1.005.00) 1.50 (1.005.00) 1.50 (1.006.00) 1.50 (1.002.00) 1.00 (1.002.00) 1.30 (1.001.50) 1.00 (0.502.00) 1.30 (1.001.50) 2.50 (1.004.00) 1.50 (1.002.50) 1.50 (0.802.00) 1.50 (0.803.00) 1.00 3.20 ± 0.86 3.50 ± 0.45 2.80 ± 1.60 2.10 ± 0.70 1.88 ± 0.21

2.10 ± 1.00 2.50 ± 2.50 2.30 ± 1.70

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14.90 76

15.823 ± 4.090

20.675 ± 5.700

12.50 ± 2.20

77

3.139 ± 0.935

4.059 ± 1.105

16.30 ± 4.80

77

77

6.357 ± 1.431

8.225 ± 1.947

76

13.70 ± 2.10

77

77

22.583 ± 7.343

30.995 ± 11.146

14.90 ± 4.80

77

0.103

8.10 ± 4.80

78

0.489

12.10 ± 7.80

78

0.939

12.20 ± 4.70

78

2.093

12.10 ± 7.00

78

3.801

8.50

79

0.699

8.80

80

1.772

8.20

80

7.169

8.70

80

6.400 2.968 ± 0.283 2.810 ± 0.405 171.100 ± 59.900 143.300 ± 84.700 0.706 ± 0.063

2.584 ± 1.305 2.325 ± 0.639 1.898 ± 0.664

81

10.40 ± 1.80 9.00 ± 1.30 12.50 ± 2.30 14.20 ± 4.10 3.28 ± 0.21 4.70 ± 0.40 4.20 ± 2.70 4.00 ± 0.90 4.20 ± 1.50

82

82

83

83

84

85

86

86

86

glycated hemoglobin by 0.6−1.2% (7−13 mmol/mol) either as monotherapy or in combination with

Accepted Article

other anti-diabetic drugs.33 Α-GLUCOSIDASE INHIBITORS (AGIS)

AGIs (Figure 7) are oral antidiabetic agents that delay the breakdown of complex carbohydrates in the small intestine and slow down glucose absorption, which leads to a slower rise in blood glucose level ( Table 1).36 AGIs are the most effective anti-diabetic agent primarily in targeting postprandial

hyperglycaemia.36 Compared to metformin or the sulfonylureas, AGIs are less effective in lowering

hyperglycaemia, reducing HbA1C level by 0.5−0.8%.36 Hypoglycaemia is not often observed in AGIs as they do not increase insulin secretion; however, increased delivery of carbohydrate to the colon was commonly observed which resulted in an increase in gas production and gastrointestinal symptoms such as flatulence and diarrhea.36,37 AGIs may be used as monotherapy in combination with an appropriate diabetic diet and exercise, or they may be used in conjunction with other antidiabetic drugs.

Clinically used AGIs include acarbose (first approved, Precose in North America, Glucobay in

China and Europe, and Prandase in Canada), emiglitate, miglitol (Glycet), and voglibose. Only acarbose and miglitol are available in the US. Acarbose is an adjunct to diet and exercise in T2DM patients whose glycemic control is not achieved. All AGIs act on α-glucosidase enzymes. However, acarbose is most effective on glucoamylase inhibition whilst miglitol is a more potent inhibitor of disaccharide-digesting enzymes.36 Acarbose inhibits α-glucosidase enzymes in the brush border of the small intestines and pancreatic α-amylase. Moreover, new AGIs are still developed to improve

the efficacy and safety.38 Interestingly, AGIs are frequently prescribed as first-line agents in Asian countries with diet rich in complex carbohydrates, but are seldom prescribed in the US and Europe with protein and fat rich diet. AGIs are generally well tolerated.

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Accepted Article

GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONISTS So far, there are at least five GLP-1 agonists approved and used for the treatment of T2DM worldwide. Exenatide (Byetta) was the first GLP-1 analogue launched and was approved by the FDA in April 2005 and the EMEA in September 2006. It was developed from exendin-4, found in the saliva of the Gila monster lizard and has ∼50% homology with human GLP-1. Liraglutide (Figure 8, Victoza) has 97% homology with GLP-1 and was approved by the FDA in January 2010. Two more GLP-1 analogues, albiglutide developed by GlaxoSmithKline and taspoglutide developed by Roche. However, the Phase III clinical trial of taspoglutide has been halted due to the incidences of serious hypersensitivity reactions and gastrointestinal side effects.39

MEGLITINIDES/GLINIDES (POTASSIUM CHANNEL MODULATOR)

Meglitinides (Figure 9) stimulate rapid insulin secretion from β-cells by inhibiting ATP-sensitive K+ channel and activating the voltage-dependent Ca2+ channel (

Table 1). The extent of insulin release stimulated by meglitinides is glucose-dependent and diminishes at low glucose levels.40 Unlike sulfonylureas, meglitinides act on a non-sulfonylureas binding site on the pancreatic β-cells. Meglitinides are indicated as adjuncts to diet and exercise to improve glycaemic control in adults with T2DM. Meglitinides are not recommended as monotherapy, however, may be added to metformin therapy for those patients with continued postprandial hyperglycaemia.

Repaglinide (Prandin), a benzoic acid derivative, was the first meglitinide analogue available

since December 1997 in the US.41 The rapid onset of action, glucose-dependent insulin secretion

effect of repaglinide makes this agent suitable for pre-prandial administration. In addition, repaglinide causes early-phase insulin secretion which allows patients to have flexible mealtimes without increasing the risk of hypoglycaemia or compromising glycaemic control.41 As with

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sulfonylureas, the major side effect or repaglinide is hypoglycaemia. Nateglinide (Starlix) was

Accepted Article

approved by the FDA in December 2000. Nateglinide is used with diet and exercise to control blood glucose levels in patients with T2DM.42,43 Nateglinide promotes a more rapid but less

sustained secretion of insulin than other available oral anti-diabetic agents. It is most effective when administered in a dose of 120 mg, 1−10 min before a meal. Combination studies with metformin (Glucophage) have shown it to be effective in controlling hyperglycaemia.42 While metformin

reduces the basal plasma glucose, nateglinide helps in controlling post-prandial peaks. It can also be used in combination with pioglitazone (Actos) or rosiglitazone (Avandia). Mitiglinide is the third meglitinide mainly targeting postprandial hyperglycaemia.44 However, it has not gained approval from the FDA. Mitiglinide exhibits a rapid onset and short duration of action, mimicking a physiologic pattern of insulin release in non-diabetic people.44 This drug modestly decreased HbA1c,

postprandial hyperglycaemia, oxidative stress and inflammatory markers associated with postprandial hyperglycaemia. Mitiglinide is well tolerated.

SODIUM-GLUCOSE COTRANSPORTER-2 (SGLT-2) INHIBITORS

SGLT-2 inhibitors (Figure 10) function via lowering the threshold for glycosuria and correcting the hyperglycaemia.45,46 Inhibition of SGLT-2 results in the normalization of the blood glucose level and amelioration of insulin resistance through augmenting insulin signaling and increasing GLUT4 and glycogen synthase activity in muscle.45,46 In the liver, correction of hyperglycaemia decreases the activities of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, which in turn results in a reduction in gluconeogenesis, total hepatic glucose production, and fasting plasma glucose concentration.45,46 Furthermore, correction of the hyperglycaemia is able to improve β-cell

function ( Table 1).45,46

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Clinical trials of SGLT-2 inhibitors in patients with T2DM demonstrate a significant clinical

Accepted Article

effect in decreasing serum glucose, HbA1C, body weight, systolic blood pressure, improving β-cell function, and minimizing the risk of hypoglycaemia.47 Canagliflozin (Invokana) is the first SGLT-2

inhibitor48 that gained FDA approval in March 2013 and gained a grant from the EMEA in

September 2013. Canagliflozin is indicated as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM.49,50 It corrects a novel pathophysiological defect, has an insulinindependent action, reduces HbA1c by 0.5−1.1%, promotes weight loss, has a low incidence of hypoglycaemia, complements the action of other anti-diabetic agents, can be used at any stage of diabetes, and appears to be safe in patients with impaired renal function. Due to the side effects such as urinary tract and genital infections and hypotension, proper patient selection for drug initiation and close monitoring will be important.50 Dapagliflozin (Foxiga) has been approved by

the EMEA and is already in the market in several European countries, but the FDA rejected the approval of dapagliflozin based on the lack of clinical data to effectively assess the benefit-to-risk profile. Dapagliflozin can be used in combination with other anti-hyperglycaemic agents and at all stages of the disease.

Several other SGLT-2 inhibitors are currently in Phase I, II or III clinical trials; including

ISIS388626, GW869682, EGT0001442, ertugliflozin, sergliflozin, ipragliflozin, empagliflozin, tofogliflozin, and luseogliflozin (Table 2). In healthy volunteers and T2DM patients, oral administration of sergliflozin produces rapid and sustained suppression of renal glucose reabsorption and dose-dependent glucosuria.51,52 Ipragliflozin (ASP1941) is an SGLT-2 inhibitor in

Phase III clinical development for the treatment of T2DM.53-55 Ipragliflozin significantly reduced

glycosylated hemoglobin, fasting plasma glucose, and amplitude of glucose excursions, with good safety profiles.56,57 Empagliflozin is a newly developed selective SGLT-2 inhibitor for the treatment of T2DM as monotherapy or combination therapy with other anti-diabetic agents.58,59 Empagliflozin

was well tolerated in T2DM patients.60

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Accepted Article

SULFONYLUREAS

Sulfonylureas have long been established in the treatment of T2DM since the 1950s and were the first oral anti-diabetic medications to be introduced into clinical practice. They are still widely used and are the second-line recommended choice of oral hypoglycaemic treatment after metformin.61

Sulfonylureas are insulin secretagogues that bind to sulfonylurea receptor (SUR1) on functional β-

cells, causing the closure of ATP-sensitive K+ channels, which leads to depolarization, an influx of Ca2+, and insulin secretion ( Table 1).62,63 Tolbutamide and gliclazide block channels containing SUR1 (β-cell type, encoded by

the ABCC8 gene), but not SUR2A (cardiac & skeletal muscle type) or SUR2B (smooth muscle and adipose tissue, both encoded by the ABCC9 gene), whereas glibenclamide, glimepiride, repaglinide, and meglitinide block both types of channels.62,64 Sulfonylureas used as monotherapy can reduce HbA1C level by ~1.51% (corresponding to 17 mmol/mol glucose decrease), which is comparable to

that of metformin.65 Sulfonylureas added to oral diabetes treatment reduced HbA1c level by 1.62% (18 mmol/mol) compared with the other treatment, and sulfonylurea added to insulin lowered HbA1c by 0.46% (6 mmol/mol) and lowered insulin dose. 65 Sulfonylureas may also reduce hepatic clearance of insulin, further increasing plasma insulin level.

The first generation sulfonylureas include tolbutamide, acetohexamide, carbutamide,

metahexamide, tolazamide, and chlorpropamide (Figure 11), and they are rarely used presently due to the severe side effects. The major side effects induced by sulfonylureas include hypoglycaemia or even coma and binding to the cardiac receptors, resulting in failure of coronary vasodilatation and subsequent deleterious cardiac effects due to low specificity of the biological action, delayed time of onset, the long duration of the effect.66 Second generation sulfonylureas exhibit a safer and

better biological profile accomplished by selective binding and rapid onset of actions. These

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improvements will attend to sulfonylurea-induced hypoglycaemia and cardiovascular side effects.

Accepted Article

This group includes glibenclamide (glyburide, Diabeta, Glynase, and Micronase), glibornuride, glipizide (Glucotrol), gliquidone, glisoxepide, glyclopyramide (Deamelin-S), glimepiride (Amaryl), and gliclazide (not marketed in US) (Figure 12).

THIAZOLIDINEDIONES/GLITAZONES (TZDS) AND DUAL PPARα & Γ AGONISTS (GLITAZARS)

TZDs (Figure 13) act as PPARs agonists lowering plasma glucose, triglyceride, and fatty acid levels in patients with T2DM ( Table 1). There are three distinct PPARs which have been identified, including PPARα, PPARδ (also called PPARβ, NUC-1 or FAAR), and PPARγ, with substantial differences in the tissue distribution, ligand binding, and metabolic regulation.67,68 PPARα is the most abundant in brown adipose tissue, and liver; but a lesser extent in the kidney, heart, and skeletal muscle.67 PPARδ is widely distributed but is mainly expressed in the gut, kidney, and heart.69 PPARγ is mainly

expressed in the adipose tissue, then in the enteric system, immune system, and the retina.67

An older TZD troglitazone was withdrawn from the market in March 2000 due to fatal

idiosyncratic hepatotoxicity. Other TZDs including rosiglitazone, pioglitazone, and rivoglitazone have not shown the same problems but patients should be closely monitored for possible liver problem.70,71 Hypoglycaemia associated with TZD (rosiglitazone) is low (≤2%) because they do not

stimulate insulin secretion which is similar to biguanides. TZDs are contraindicated in patients with severe heart failure or liver disease. Glitazones have only a modest effect on dyslipidaemia, and they increase fat mass and plasma volume; fibrate PPARα activators decrease plasma triglycerides and increase HDL-cholesterol levels; and PPARδ activators increase the capacity for fat oxidation in skeletal muscle.72 These have encouraged attempts to develop single molecules that activate two

or all three PPARs. Many dual PPARα & γ agonists such as aleglitazar, muraglitazar, saroglitazar, This article is protected by copyright. All rights reserved.

and tesaglitazar are under development, and they reduce both hyperglycaemia and dyslipidaemia.72

Accepted Article

However, their development has been hampered by issues such as increased weight gain, edema, plasma creatinine, and myocardial infarction or stroke, and cancer risk. In June 2013, saroglitazar developed by the Zydus Cadila was the first glitazar to be approved by the Drug Controller General of India for treatment of T2DM. It is marketed under the trade name Lipaglyn. The average terminal half-life of saroglitazar was 5.6 hr and was not eliminated via the renal route.73 Single oral

doses of saroglitazar up to 128 mg were well tolerated.73 Bezafibrate (marketed as Bezalip and

various other brand names) is a fibrate drug used for the treatment of hyperlipidaemia. It helps to lower LDL cholesterol and triglyceride and increase HDL in the blood. Like the other fibrates, bezafibrate is an agonist of PPARα; some studies also suggest it may have modulating effect on PPARγ and PPARδ as well.74

CONCLUSIONS AND FUTURE DIRECTIONS

Despite the fact that a variety of anti-diabetic agents are available for T2DM patients, there are shortcomings in diabetes treatment presently and the search for optimal therapy is necessary. Putting aside common side effects such as weight gain and hypoglycaemia, current diabetes therapies does not address the key driver of this condition, β-cell dysfunction and does not alter the progressive nature of insulin secretory deficit. Additionally, the pathophysiology of the disease is only partially understood and there are currently no anti-diabetic agents that can effectively reduce excessive cardiovascular risk associated with T2DM.

Current diabetes therapies lower blood glucose but they do not address the key driver of this

condition, β-cell dysfunction, and do not alter the progressive nature of insulin secretory deficit in T2DM. Additionally, the pathophysiology of the disease is only partially understood. Furthermore, no current anti-diabetic agents can effectively reduce excessive cardiovascular risk. Therefore, development of new anti-diabetic drugs should not only attend to blood glucose level, but also aim

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to halt disease progression, restore β-cell function, and in the long run, reduce T2DM associated

Accepted Article

complications such as cardiovascular risks. Acknowledgements The authors appreciate the financial support from the Startup Funds of the College of Pharmacy, University of South Florida, Tampa, Florida, USA and Guizhou Medical University, Guiyang, Guizhou, China. Dr. Zhi-Wei Zhou is a holder of a postdoctoral scholarship from College of Pharmacy, University of South Florida, Tampa, Florida, USA. The authors appreciate the help from Mr. Jeffrey L. Edelman from University of South Florida (Tampa, FL) for manuscript proof reading.

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Table 1. Mechanisms of action of oral antidiabetic drugs. Drug

Class

Tolrestat Epalrestat Fidarestat Ranirestat Ponalrestat

Aldose reductase inhibitors

Sorbinil Risarestat

Benfluorex

Anorectic

Buformin Metformin Biguanides

Phenformin Alogliptin Gemigliptin

Linagliptin

Saxagliptin

Sitagliptin

Dipeptidyl peptidase 4 inhibitors

Mechanism of action Tolrestat, an aldose reductase inhibitor, completely inhibits the production of sorbitol in cells. Epalrestat inhibits the reduction of glucose to sorbitol. Fidarestat blocks the production of sorbitol. Ranirestat functions by reducing sorbitol accumulation in cells. Ponalrestat, a potent and specific inhibitor of aldose reductase, inhibits the production of sorbitol in cells. Sorbinil inhibits the first enzyme of the polyol pathway, which is activated when glucose levels are high, and can damage cells by multiple mechanisms. Risarestat reduces the production of sorbitol in cells. Benfluorex inhibits gluconeogenesis is, at least in part, ascribed to a decrease in mitochondrial β-oxidation. Benfluorex decreases acetyl-CoA concentration, reducing pyruvate carboxylase activity and release its inhibitory effect on pyruvate dehydrogenase. Benfluorex also decreases both the ATP/ADP and the NAD+/NADH ratios, leading to a reduced gluconeogenic flux at the level of 3phosphoglycerate kinase and GAPDH. Buformin activates AMPK, increasing insulin sensitivity. Metformin decreases blood glucose levels by reducing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization. These effects are mediated by the activation of AMPK. Phenformin binds to AMPK. Phenformin has been shown to independently decrease ion transport processes, influence cellular metabolism and activate AMPK. It also seems to inhibit several varients of KATP channel. Alogliptin inhibits DPP-4. The inhibition of DPP-4 increases the amount of active plasma incretins which helps with glycemic control. Gemigliptin inhibits DPP-4 which in turn increases the amount of active plasma incretins and helps with glycemic control. Linagliptin is a competitive and reversible DPP-4 inhibitor that slows the breakdown of insulinotropic hormone GLP-1 for better glycemic control in diabetes patients. This results in an overall decrease in glucose production in the liver and an increase in insulin in a glucose-dependent manner. Saxagliptin is a DPP-4 inhibitor for the treatment of T2DM. Saxagliptin forms a reversible, histidine-assisted covalent bond between its nitrile group and the S630 hydroxyl oxygen on DPP-4. The inhibition of DPP-4 increases levels active of GLP1, which inhibits glucagon production from pancreatic α-cells and increases production of insulin from pancreatic β-cells. Sitagliptin is a highly selective DPP-4 inhibitor, which is believed to exert its actions in patients with T2DM by slowing the inactivation of incretin hormones,

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Accepted Article

Vildagliptin Bromocriptine

Dopamine D2 receptor agonist

Acarbose Miglitol

α-Glucosidase inhibitors

Voglibose Mitiglinide

Nateglinide Meglitinides

Repaglinide

Canagliflozin Dapagliflozin Empagliflozin

SGLT-2 inhibitors

Remogliflozin Sergliflozin Tofogliflozin

Acetohexamide

Carbutamide

Chlopropamide

Metahexamide

Tolbutamide

Tolazamide

Glibenclamide

Glibornuride

Sulfonylureas

including GLP-1 and GIP, thereby increasing the concentration and prolonging the action of these hormones. Vildagliptin inhibits DPP-4 which in turn inhibits the inactivation of GLP-1 by DPP-4, allowing GLP-1 to potentiate the secretion of insulin in the β-cells. Stimulation of dopamine D2 receptor causes inhibition of adenylyl cyclase, decreasing intracellular cAMP concentrations and blocking IP3-dependent release of Ca2+ from intracellular stores. Acarbose reversibly binds to pancreatic α-amylase and membrane-bound intestinal α-glucoside hydrolases in the brush border of the small intestine. Miglitol does not enhance insulin secretion. The antihyperglycemic action of miglitol results from a reversible inhibition of membrane-bound intestinal αglucoside hydrolase enzymes. Voglibose act as competitive inhibitors of α-glucosidase enzymes in the brush border of the small intestines. Mitiglinide is thought to stimulate insulin secretion by binding to and blocking KATP in pancreatic β-cells. Nateglinide activity is dependent on the presence functioning β-cells and glucose. Nateglinide has no effect on insulin release in the absence of glucose. It potentiates the effect of extracellular glucose on the KATP channel and has little effect on insulin levels between meals and overnight. Repaglinide activity is dependent on the presence functioning β-cells and glucose. Repaglinide has no effect on insulin release in the absence of glucose. It potentiates the effect of extracellular glucose on KATP channel and has little effect on insulin levels between meals and overnight. Canagliflozin is an inhibitor of SGLT-2. By inhibiting SGLT-2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose and thereby increases urinary glucose excretion. Dapagliflozin, a competitive inhibitor of the SGLT-2, blocks glucose reabsorption into the kidney, resulting in the elimination of blood glucose through the urine. Empagliflozin inhibits SGLT-2, reducing the reabsorption of glucose in the kidney. Remogliflozin blocks SGLT-2 resulting in the decrease in the reabsorption of glucose in the kidney. Sergliflozin blocks SGLT-2 causing the reduction in the reabsorption of glucose in the kidney. Tofogliflozin binds to SGLT-2 resulting in the inhibition in the reabsorption of glucose in the kidney. Acetohexamide binds to the KATP channel on the cell membrane of pancreatic βcells. This inhibits a tonic, hyperpolarizing outflux of potassium, which causes the electric potential over the membrane to become more positive. This depolarization opens voltage-gated Ca2+ channel. The rise in intracellular calcium leads to increased fusion of insulin granulae with the cell membrane, and therefore increased secretion of (pro) insulin. Carbutamide blocks the KATP channel on the β-cell resulting in the depolarization and calcium influx, calcium-calmodulin binding, kinase activation, and release of insulin-containing granules by exocytosis, an effect similar to that of glucose. Chlorpropamide binds to the KATP channel on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive Ca2+ channel, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin. Metahexamide blocks the KATP channel on the β-cell leading to the depolarization and calcium influx, calcium-calmodulin binding, kinase activation, and release of insulin-containing granules by exocytosis, an effect similar to that of glucose. Tolbutamide inhibits the KATP channels on the β-cell membrane and potassium efflux, which results in depolarization and calcium influx, calcium-calmodulin binding, kinase activation, and release of insulin-containing granules by exocytosis, an effect similar to that of glucose. Tolazamide likely binds to KATP channel on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive Ca2+ channel, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin. Glibenclamide binds to KATP channel on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive Ca2+ channel, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin. Glibornuride blocks KATP channel, reducing potassium conductance and causing depolarization of the membrane.

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Accepted Article

Gliclazide

Glimepiride

Glipizide

Gliquidone

Glisoxepide

Glyclopyramide Pioglitazone Rivoglitazone

Rosiglitazone

Thiazolidinedione

Troglitazone

Gliclazide binds to the β-cell sulfonyl urea receptor. This binding subsequently blocks the KATP channel. The binding results in closure of the channel and leads to a resulting decrease in potassium efflux leads to depolarization of the β-cells. This opens voltage-dependent Ca2+ channel in the β-cell resulting in calmodulin activation, which in turn leads to exocytosis of insulin containing secretorty granules. The mechanism of action of glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic β- cells, and increasing sensitivity of peripheral tissues to insulin. Glimepiride likely binds to KATP channel on the pancreatic β-cell surface, reducing potassium conductance and causing depolarization of the membrane. Glipizide likely binds to KATP channel on the pancreatic β-cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive Ca2+ channel, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin. The mechanism of action of gliquidone in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic β-cells, and increasing sensitivity of peripheral tissues to insulin. Gliquidone likely binds to KATP channel on the pancreatic β-cell surface, reducing potassium conductance and causing depolarization of the membrane. Glisoxepide is a hypoglycemic sulphonylurea agent, acting via the augmentation of secretion of insulin from pancreatic β-cells. Glisoxepide functions as a non-selective KATP channel blocker. It is thought to stimulate insulin secretion by closing the KATP channel in pancreatic β-cells. Glyclopyramide inhibits the KATP channel in pancreatic β-cells, stimulating insulin secretion. Pioglitazone acts as an agonist at PPAR in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Pioglitazone both enhances tissue sensitivity to insulin and reduces hepatic gluconeogenesis. Rivoglitazone, a PPAR-γ agonist, enhances tissue sensitivity to insulin and reduces hepatic gluconeogenesis. Rosiglitazone acts as a highly selective and potent agonist at PPAR in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-γ receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. Troglitazone lowers blood glucose by improving target cell response to insulin. It has a unique mechanism of action that is dependent on the presence of insulin for activity. Troglitazone decreases hepatic glucose output and increases insulin dependent glucose disposal in skeletal muscle. Its mechanism of action is thought to involve binding to PPAR that regulate the transcription of a number of insulin responsive genes critical for the control of glucose and lipid metabolism.

Abbreviation: AMPK, 5'-adenosine monophosphate-activated protein kinase; DPP-4, dipeptidyl peptidase 4; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide-1; KATP, ATPsensitive potassium; PPAR, peroxisome proliferator-activated receptor; SGLT-2, sodium-glucose cotransporter-2.

Table 2. Clinical pharmacokinetics of selected oral antidiabetic drugs. Drug Alogliptin

Subject

Dosage

13 patients

25 mg/q.d. (Day 1)

Cmax (mg/L) 0.146 ± 0.059

13 patients

25 mg/q.d. (Day 14)

0.153 ± 0.039

14 patients

100 mg/q.d. (Day 1)

0.630 ± 0.276

14 patients

100 mg/q.d.

0.742 ±

Tmax (hr)

AUC(mg/L•hr)

1.30 (0.806.20) 1.10 (0.804.50) 1.30 (0.506.40) 1.00

1.058 ± 0.165

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1.474 ± 0.214

t1/2 (hr)

76

21.10 ± 8.80

76

76

4.917 ± 1.166

6.804 ± 2.866

Reference

20.00 ±

76

Accepted Article

Canagliflozin

Dapagliflozin

Empagliflozin

Epalrestat Glibenclamide

Gliclazide

Glimepiride Glipizide

(Day 14)

0.578

15 patients

400 mg/q.d. (Day 1)

2.420 ± 1.130

14 patients

400 mg/q.d. (Day 14)

2.560 ± 0.791

9 patients

50 mg/q.d. (Day 1)

0.426 ± 0.106

9 patients

50 mg/q.d. (Day 7)

0.536 ± 0.174

8 patients

100 mg/q.d. (Day 1)

1.096 ± 0.444

8 patients

100 mg/q.d. (Day 7)

1.227 ± 0.481

10 patients

300 mg/q.d. (Day 1)

3.480 ± 0.844

10 patients

300 mg/q.d. (Day 7)

4.678 ± 1.685

6 HV

2.5 mg/q.d.

0.029

6 HV

10 mg/q.d.

0.124

6 HV

20 mg/q.d.

0.265

6 HV

50 mg/q.d.

0.610

16 HV

50 mg/q.d.

0.532

16 patients

10 mg/b.i.d.

0.139

16 patients

25 mg/b.i.d.

0.326

30 patients

100 mg/b.i.d.

1.186

HV 110 patients

50 mg/q.d. 20 mg/q.d.a

110 patients

20 mg/q.d.c

9 Caucasian patients 10 aboriginal patients 8 patients

160 mg/q.d.b 160 mg/q.d.b 2 mg/q.d.

3.900 0.354 ± 0.033 0.360 ± 0.049 15.000 ± 3.700 14.100 ± 5.100

6 patients

10 mg/q.d.

10 HV (≤ age 25) 10 HV (≥ age 65) 15 patients (≥ age 65)

10 mg/q.d.a 10 mg/q.d.a 10 mg/q.d.a

1.8002.300 0.465 ± 0.146 0.399 ± 0.101 0.385 ± 0.150

(0.6010.60) 1.00 (0.502.50) 1.10 (0.504.50) 2.00 (1.004.00) 2.00 (1.005.00) 1.50 (1.005.00) 1.50 (1.005.00) 1.50 (1.006.00) 1.50 (1.002.00) 1.00 (1.002.00) 1.30 (1.001.50) 1.00 (0.502.00) 1.30 (1.001.50) 2.50 (1.004.00) 1.50 (1.002.50) 1.50 (0.802.00) 1.50 (0.803.00) 1.00 3.20 ± 0.86 3.50 ± 0.45 2.80 ± 1.60 2.10 ± 0.70 1.88 ± 0.21

2.10 ± 1.00 2.50 ± 2.50 2.30 ± 1.70

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14.90 76

15.823 ± 4.090

20.675 ± 5.700

12.50 ± 2.20

77

3.139 ± 0.935

4.059 ± 1.105

16.30 ± 4.80

77

77

6.357 ± 1.431

8.225 ± 1.947

76

13.70 ± 2.10

77

77

22.583 ± 7.343

30.995 ± 11.146

14.90 ± 4.80

77

0.103

8.10 ± 4.80

78

0.489

12.10 ± 7.80

78

0.939

12.20 ± 4.70

78

2.093

12.10 ± 7.00

78

3.801

8.50

79

0.699

8.80

80

1.772

8.20

80

7.169

8.70

80

6.400 2.968 ± 0.283 2.810 ± 0.405 171.100 ± 59.900 143.300 ± 84.700 0.706 ± 0.063

2.584 ± 1.305 2.325 ± 0.639 1.898 ± 0.664

81

10.40 ± 1.80 9.00 ± 1.30 12.50 ± 2.30 14.20 ± 4.10 3.28 ± 0.21 4.70 ± 0.40 4.20 ± 2.70 4.00 ± 0.90 4.20 ± 1.50

82

82

83

83

84

85

86

86

86

32 patients

30 mg/q.d.

Linagliptin

184 HV

0.5-600 mg/q.d. 5 mg/q.d.

Accepted Article

Gliquidone

41 patients

0.650 (0.1202.140) 0.0022.050 0.050 ± 0.030 1.018

Metformin

13 patients

Mitiglinide

8 HV

500 mg/b.i.d. 5 mg/q.d.a

8 HV

5 mg/q.d.b

8 HV

10 mg/q.d.a

8 HV

10 mg/q.d.b

8 HV

20 mg/q.d.a

8 HV

20 mg/q.d.b

6 HV 6 HV

120 mg/q.d. 45 mg/q.d.

6 patients with moderate renal impairment 6 patients with severe renal impairment 33 patients

45 mg/q.d.

1.337 ± 0.363

45 mg/q.d.

1.123 ± 0.295

34 patients

20 mg/q.d.

Remogliflozin

13 patients

500 mg/b.i.d.

2.689

Rosiglitazone

32 HV

1 mg/q.d.a

32 HV

2 mg/q.d.a

32 HV

8 mg/q.d.a

32 HV

8 mg/q.d.b

7 HV

5 mg/q.d.

8 HV

15 mg/q.d.

8 HV

50 mg/q.d.

8 patients

50 mg/q.d.

8 HV

100 mg/q.d.

7 patients

150 mg/q.d.

8 HV

200 mg/q.d.

7 HV

500 mg/q.d.

0.076 ± 0.013 0.156 ± 0.042 0.598 ± 0.117 0.432 ± 0.092 0.007 (0.0050.010) 0.021 (0.0160.026) 0.084 (0.0570.122) 0.096 (0.0730.125) 0.128 (0.0930.177) 0.363 (0.2210.595) 0.350 (0.2950.414) 0.845

Nateglinide Pioglitazone

Ranirestat

Sergliflozin

0.565 ± 0.110 0.224 ± 0.065 1.874 ± 0.628 0.657 ± 0.269 2.635 ± 0.901 0.913 ± 0.345 5.690 1.329 ± 0.667

5 mg/q.d.

5.100 (1.50010.100)

1.50

0.065 ± 0.015

89

4.00 (1.00-6.00 0.36 ± 0.16 1.75 ± 0.92 0.29 ± 0.19 1.97 ± 0.81 0.30 ± 0.10 1.18 ± 0.68 ≤1.00 2.00 (1.004.00) 1.00 (1.004.00) 2.00 (1.004.00) 0.5011.00 0.5011.00 3.00 (1.004.00)

7.141 (4.0008.700) 0.762 ± 0.141

90

0.030-15.599

91

14.466

9.70 ± 3.60

93

13.476

8.00 ± 3.00

93

22.0080.00 22.0080.00

94

0.746 ± 0.193 2.440 ± 0.184 2.200 ± 0.573 3.610 ± 0.873 3.773 ± 1.075 11.800 17.387

2.971 ± 0.730 2.890 ± 0.795

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3.16 ± 0.72 3.15 ± 0.39 3.37 ± 0.63 3.59 ± 0.70

0.095 (0.0800.113) 0.152 (0.0120.193) 0.169 (0.1240.231) 0.452 (0.3210.636) 0.502 (0.3920.642) 1.154 (0.922-

91

91

91

91

92 93

94

95

95

95

95

52

0.003 (0.0010.006) 0.018 (0.0130.025)

91

90

6.814

0.733 ± 0.184

0.50 (0.251.50) 1.10 (0.352.00) 0.75

88

1.19 ± 0.22 1.21 ± 0.18 1.58 ± 0.36 1.60 ± 0.65 1.43 ± 0.19 2.03 ± 1.90 1.50 13.70 ± 5.70

0.358 ± 0.112

0.50 (0.351.00) 0.75 (0.353.00) 0.75 (0.502.50) 0.75 (0.252.00) 0.75 (0.80-2.0)

8.00 (5.709.40) 55.40184.00

87

2.25 (1.254.75) 0.73-6.00

0.44 (0.240.83) 1.09 (0.961.23) 1.39 (1.071.81) 1.06 (0.881.26) 1.37 (1.181.60) 1.32 (1.121.54 1.26

52

52

52

52

52

52

52

500 mg/q.d.

Sorbinil

16 HV

250 mg/q.d.

Tolbutamide

10 HV

500 mg/q.d.

Troglitazone

20 HV

400 mg/q.d.a

20 HV

400 mg/q.d.b

12 HV

400 mg/q.d.a

12 HV

400 mg/q.d.b

12 HV

400 mg/q.d.c

20 HV

400 mg/q.d.a

20 HV

400 mg/q.d.b

6 HV

400 mg/q.d.b

8 HV

400 mg/q.d.b

8 HV

400 mg/q.d.b

58-151 HV

50 mg/q.d.

Accepted Article

7 patients

Vildagliptin

(0.6021.185) 0.912 (0.5271.579) 5.810 ± 0.280 63.000 ± 11.000 1.050 (0.2801.920) 1.380 (0.5704.060) 1.100 (0.3003.900) 2.200 (0.9003.800) 2.000 (0.8003.700) 1.060 (0.4401.810) 1.960 (0.4504.010) 0.770 (0.3801.650) 0.730 (0.3801.200) 0.370 (0.1600.790) 0.119

(0.752.00) 0.75 (0.51.25) 5.90 ± 1.30 3.30 (1.606.00) 1.75 (1.004.00) 3.41 (1.0012.00) 1.50 (0.754.00) 1.50 (0.502.00) 2.00 (1.504.00) 1.60 (0.504.00) 3.70 (2.0012.00 4.20 (2.006.00) 3.70 (1.008.00) 5.50 (2.0016.00) 3.00

1.444) 1.681 (1.2152.326) 0.538 ± 0.038 798.000 ± 102.000

(1.181.34) 1.33 (1.141.56) 67.70 ± 4.60 9.10

52

96

97

8.500 (1.30016.000)

98

11.400 (4.50020.700)

98

7.200 (1.30024.600)

98

11.400 (4.00021.200)

98

11.500 (4.00025.200)

98

9.300 (4.70016.400)

98

17.100 (7.80027.900)

98

13.200 (3.40042.200) 13.600 (3.60023.100) 5.990 (2.10017.800) 1.334

15.90 (4.3053.70) 24.00 (6.6070.40) 9.90 (3.8022.90) 13.10

98

98

98

99

a

: administered to fasted participants. : administered with food. c : administered 30 minutes after a meal. b

ABBREVIATION: AUC, AREA UNDER THE PLASMA CONCENTRATION-TIME CURVE; CMAX, MAXIMUM PLASMA CONCENTRATION OBSERVED; HV, HEALTH VOLUNTEER; T1/2, HALF-LIFE OF ELIMINATION, TMAX, TIME TO REACH CMAX.

FIGURE LEGENDS

Figure 1. The chemical structures of ARIs, including tolrestat, epalrestat, fidarestat, ranirestat, ponalrestat, sorbinil, and risarestat.

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Figure 2. The chemical structure of benfluorex, an anorectic and hypolipidemic agent.

Figure 3. The chemical structures of buformin, metformin, and phenformin.

Figure 4. Proposed mechanisms of action of metformin. Metformin acts through the activation of AMP-activated protein kinase in the liver and skeletal muscle and modulation of microbiota metabolism, resulting in the decrease in gluconeogenesis, glycogenesis, and fatty acid oxidation. Eventually, it leads to a reduction in blood glucose levels.

Figure 5. The chemical structures of DPP-4 inhibitors, including alogliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin.

Figure 6. The chemical structure of bromocriptine, a central-acting dopamine D2 receptor agonist.

Figure 7. The chemical structures of AGIs, including acarbose, miglitol, and voglibose.

Figure 8. The chemical structure of liraglutide, a GLP-1 agonist.

Figure 9. The chemical structures of meglitinides, including mitiglinide, nateglinide, and repaglinide.

Figure 10. The chemical structures of SGLT-2 inhibitors, including canagliflozin, dapagliflozin, empagliflozin, remogliflozin, sergliflozin, and tofogliflozin.

Figure 11. The chemical structures of the first generation sulfonylureas, including acetohexamide, carbutamide, chlorpropamide, metahexamide, tolbutamide, and tolazamide.

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Figure 12. The chemical structures of second generation sulfonylureas, including glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, and glyclopyramide.

Figure 13. The chemical structures of TZDs, including pioglitazone, rivoglitazone, rosiglitazone, and troglitazone.

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